ABSTRACT The ongoing outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major threat to global health. The nasal passages are the key portal of entry for airway virus infections, and evidence suggests that the nasal epithelium is a key reservoir for SARS-CoV-2 and a source of viral shedding that accounts for high transmissibility and elevated rates of COVID-19. We hypothesize that diminished interferon-induced innate immune responses in infected nasal epithelial cells is a primary mechanism allowing rapid viral replication without cytotoxicity. The parent grant focuses on how human sinonasal epithelial cell populations participate in immune defense and damage repair. In this supplement proposal, in response to NOT-AI-20-031, we will extend these studies to research in depth the epithelial cell innate immune response to SARS-CoV-2. Specifically, delayed interferon signaling may prevent induction of nitric oxide, which has been previously shown to inhibit viral entry and replication. Nitric oxide can be induced in nasal epithelial by stimuli other than interferon, including through activation of bitter taste receptors expressed on the cilia. There are a number of approved medications in clinical use that taste bitter and can bind to bitter taste receptors. Among these, certain anti-nausea and antihistamines are particularly strong bitter taste agonists. In this proposal, we will test the ability of these medications to inhibit SARS-CoV-2 infection of primary nasal epithelial cells in vitro. We will then use pharmacologic modulators of the bitter taste signaling and nitric oxide pathways to establish the mechanism of action of drugs that decrease infection. We will also determine if these medications impact the interferon response to SARS-CoV-2 infection. If successful, these studies may lay the foundation for novel therapeutic approaches to enhance the initial epithelial cell innate immune defense against SARS-CoV-2 infection, limiting progression of COVID-19 and decreasing transmissibility.